Field of the Invention
The present disclosure relates to inhibitors of the Notch transcriptional activation complex, and methods of using the inhibitors to decrease Notch target gene transcription and to treat and prevent diseases, such as cancer.
Description of Related Technology
The Notch pathway, a highly conserved cell signaling system present in most multicellular organisms, is widely used in development to govern cell fate specification, and to balance proliferative capacity and differentiation state. Notch drives a context-dependent cellular response by initiating and maintaining a transcriptional cascade. Notch mediates this transcriptional response by directing the formation of a core Notch transcriptional activation complex (“NTC”), which is composed of the DNA binding protein CSL, the intracellular domain of Notch (“NICD”) and the co-activator protein Mastermind (“MAML1”).
In the adult, the Notch pathway is restricted to small populations of progenitor and stem cells of regenerating tissues, such as the colon and brain. However, in many human cancers, the Notch pathway becomes reactivated. The deregulation of the Notch pathway underlies many aspects of cancer physiology, depending on cell type and context. Aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype, as well as playing a central role in cancer stem cells, which may underlie a role in metastasis and resistance to therapy.
Current compounds that regulate the Notch pathway include small molecule inhibitors that target the presenilin-dependent γ-secretase, an enzyme complex that is responsible for ligand-induced cleavage and activation of Notch, and monoclonal antibodies that inhibit ligand-receptor interactions. However, there are currently no small molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex.
Thus, there is a need for antineoplastic therapeutics capable of directly targeting the Notch transcriptional activation complex for the treatment and prevention of diseases, such as cancer.